QT Interval Research Articles

β-Adrenergic receptor signalling pathway mediated antiarrhythmic activity of s-limonene in the rat heart.

S-Limonene (s-Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s-Lim exerts its antiarrhythmic effect, focusing on the blockade of β-adrenoceptor (β-AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the β-adrenergic pathway, sarcomeric shortening and L-type calcium current (ICa,L). In isolated hearts, 10 μM of s-Lim did not alter the ECG profile or LVPD. s-Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 μM and reduced heart rate at the concentrations of 30 (12.4%) and 50 μM (16.6%). s-Lim (10 μM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 μM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s-Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker β1-AR). In vivo, s-Lim antagonized the effect of ISO (agonists β1-AR), presenting a similar effect to propranolol (a non-selective blocker β-AR). In ventricular cardiomyocyte, s-Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s-Lim did not affect changes in the ECG effect mediated by 5 μM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO-induced arrhythmia model, s-Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s-Lim is related to blockade of β-AR in the heart.

QTc prolongation across CDK4/6 inhibitors: a systematic review and meta-analysis of randomized controlled trials.

Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. We included 14 RCTs comprising 16 196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.

Clinical analysis of maternal autoantibody-mediated complete left bundle branch block in 9 children

Objective: To analyze the clinical characteristics, treatment, and outcomes of children with complete left bundle branch block (CLBBB) mediated by maternal autoantibodies. Methods: A retrospective analysis was conducted on nine children diagnosed with maternal autoantibody-mediated CLBBB, treated at Beijing Anzhen Hospital and Fujian Provincial Hospital from March 2015 to August 2023. Their clinical characteristics, electrocardiographic and echocardiographic findings before and after treatment were reviewed. Paired sample t-test was used for inter-group comparison. Results: Among the mothers, 6 had positive antinuclear antibodies (ANA), 5 had anti-Sjogren syndrome antigen A antibodies, and 3 had anti-Ro-52 antibodies. The cohort included one female and eight male children, diagnosed with CLBBB at the age of 1 (2, 13) months. The positive autoantibodies in the infants, consisted with maternal antibodies, were detected within the first 3 months of life among 3 cases. Treatments included anti-heart failure therapy, myocardial nutritional support, intravenous immunoglobulin (IVIG) and glucocorticoids. Before treatment, the levels of troponin I (0.175 (0.060, 10.270) μg/L) and N-terminal pro-B-type natriuretic peptide (420 (327, 12 865) ng/L) were elevated, which normalized in most cases after treatment. Post-treatment, the QRS duration significantly shortened compared to pre-treatment ((137±15) vs.(169±25) ms, t=3.76, P<0.001), and the QTc interval significantly decreased ((433±41) vs. (514±27) ms, t=4.95, P=0.001). Before treatment, varying degrees of mitral and tricuspid regurgitation and marked interventricular septal dyskinesia were observed in echocardiography. After treatment, valve regurgitation and ventricular septum motion significantly improved, with a marked increase in left ventricular ejection fraction ((51±13)% vs. (27±6)%, t=-6.66, P<0.001). Conclusions: Maternal autoantibody-mediated CLBBB in children presents with chronic heart failure in infancy. Early treatment with anti-heart failure medications, IVIG and glucocorticoids can improve clinical symptoms.

Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication.

Empagliflozin (EMPA) is a sodium-glucose transporter-2 inhibitor used in the treatment of type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline (AMT) can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation. Our aim in this study was to determine how the effects of the concomitant use of empagliflozin and amitriptyline, which have been shown to have effects on sodium and calcium metabolism in cardiomyocytes, would cause an effect on QT and QTc intervals in clinical practice. Twenty-four male Wistar albino rats were randomised into four groups. The control group received only physiological serum (1 ml) via orogastric gavage (OG). The EMPA group received empagliflozin (10 mg/kg) via OG. The AMT group received amitriptyline (100 mg/kg) via OG. The AMT + EMPA group (n = 6) received amitriptyline (100 mg/kg) and empagliflozin (10 mg/kg). Under anaesthesia, QT and QTc intervals were measured at baseline, and in the first and second hours. In the AMT group, QT intervals and QTc values were found to be statistically longer than in the control group (p ≤ 0.001). Empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. In the AMT + EMPA group, QT and QTc intervals were significantly lower compared to that in the AMT group (p < 0.01). In this study, we determined that empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. This effect was probably due to the opposite effects of these two agents in the intracellular calcium balance. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QT and QTc prolongation in diabetic patients receiving amitriptyline.

Arrhythmias in thyroid dysfunction

Thyroid dysfunction is associated with characteristic changes in heart rate and arrhythmias. Thyroid hormones act through genomic and non-genomic effects on myocytes and influence contractility, relaxation and action potential duration through avariety of mechanisms. Atrial fibrillation is the most common arrhythmia associated with thyroid dysfunction, it occurs in both euthyroidism and hyperthyroidism in clear association with T4 levels. Mechanistically, in the hyperthyroid state, increased automaticity and triggered activity, together with ashortened refractory period and slowing of the conduction speed, lead to the initiation and maintenance of multiple intraatrial reentry circuits. Influences from the autonomic nervous system and hemodynamics controlled by thyroid hormones act as modulators for arrhythmias, which are promoted by acorresponding substrate (significant impact of comorbidities). Concerning therapy, in addition to treating hyperthyroidism, the initial therapeutic focus is on adequate rate control and anticoagulation in patients with ahigh risk of thromboembolism. Ablation of atrial fibrillation can be considered later on, although there is an increased likelihood of recurrence compared to patients without hyperthyroidism.Prolongation of the QT interval and increase in QT dispersion are involved in the formation of ventricular arrhythmias. Epidemiological data suggest an association of elevated T4 levels with ventricular arrhythmias and sudden cardiac death. However, this seems to be mainly relevant for patients with underlying cardiac disease (e.g. ICD users).

Children and Adolescent Patients with Variants in the ATP1A3 -encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate an Impaired QT Response to Bradycardia and Predisposition to Sinus Node Dysfunction.

Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition. We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 - related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed. The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 - related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds. Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contribute to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction. What is Known: Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia. What the Study Adds: The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

Sex-Specific Differences in Cardiovascular Adaptations and Risks in Elite Athletes: Bridging the Gap in Sports Cardiology.

The growing participation of women in competitive sports necessitates a comprehensive understanding of sex-specific cardiovascular adaptations and risks. Historically, research has predominantly focused on male athletes, leaving a gap in knowledge about the unique cardiovascular dynamics of female peers. we hypothesized that female athletes exhibit distinct cardiovascular adaptations and face different risks, influenced by physiological, hormonal, and structural differences. A systematic review of the literature was conducted, analyzing studies on cardiovascular responses and adaptations in athletes. Data were extracted on hemodynamic changes, autonomic and neural reflex regulation, cardiac remodeling, and arrhythmias. Comparative analyses were performed to identify sex-specific patterns and discrepancies in cardiovascular health outcomes. We revealed considerable sex differences in cardiovascular adaptations to athletic training. Female athletes generally have longer QT intervals, greater sinoatrial node automaticity, and enhanced atrioventricular node function compared to males. They also exhibit lower sympathetic activity, lower maximal stroke volumes, and a tendency toward eccentric cardiac remodeling. Conversely, male athletes are more prone to concentric hypertrophy and higher incidences of bradyarrhythmia and accessory pathway arrhythmias. Female athletes are more likely to experience symptomatic atrial fibrillation and face higher procedural complications during catheter ablation. Our findings underscore the necessity for sex-specific approaches in sports cardiology. Recognizing and addressing these differences could enhance performance and reduce adverse cardiac events in athletes. Future research should focus on developing tailored screening, prevention, and treatment strategies to bridge the knowledge gap and promote cardiovascular health in both male and female athletes.

A phase I drug-drug interaction study to assess the effect of futibatinib on P-gp and BCRP substrates and of P-gp inhibition on the pharmacokinetics of futibatinib.

Futibatinib, an inhibitor of fibroblast growth factor receptor 1-4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug-drug interaction study, the effects of futibatinib on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates, and of P-gp inhibition on futibatinib pharmacokinetics (PK) were investigated in healthy adults aged 18-55 years. In part 1, 20 participants received digoxin (P-gp substrate) and rosuvastatin (BCRP substrate). Following a ≥10-day washout, futibatinib was administered for 7 days, with digoxin and rosuvastatin coadministered on the third day. In part 2, 24 participants received futibatinib. Following a ≥3-day washout, quinidine (P-gp inhibitor) was administered for 4 days, with futibatinib coadministered on day 4. Blood samples were collected predose and for 24 (futibatinib), 72 (rosuvastatin), and 120 h (digoxin) postdose. Urine samples (digoxin) were collected predose and for 120 h postdose. PK parameters were compared between treatments using analysis of variance. Coadministration with futibatinib had no effect on the PK of digoxin and rosuvastatin, and coadministration with quinidine had minimal effects on the PK of futibatinib. Differences in Cmax and AUC with and without futibatinib and quinidine, respectively, were <20%. The most common treatment-emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P-gp or BCRP substrates and that the effect of P-gp inhibition on futibatinib PK is not clinically relevant.

Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC. Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS). Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n= 60), PSA50 was 32% (n= 19), including 50% (n= 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations. BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.

Low foetal heart rate, a potentially ominous finding: case report

Abstract Background Congenital long QT syndrome (LQTS) type 1 is characterized by abnormally prolonged ventricular repolarization caused by inherited defects in cardiac potassium channels. Patients are predisposed to ventricular arrhythmias and even sudden cardiac death. In some cases, foetal sinus bradycardia is the only sign, making prenatal diagnosis challenging. Physicians should be aware of this subtle presentation of LQTS. Early diagnosis and proactive treatment are crucial for preventing unexpected cardiac events. Case summary A healthy and asymptomatic 25-year-old pregnant woman was referred to our institute for cardiac evaluation after persistent foetal sinus bradycardia was detected during repeated ultrasounds, despite the absence of any foetal morphological or functional cardiac anomalies. After a thorough assessment, the mother was diagnosed with LQTS type 1, as confirmed by molecular genetic testing. Appropriate management, including maternal medication and increased surveillance, was initiated. The infant was delivered safely, and his electrocardiogram revealed a significantly prolonged QTc interval. Genetic testing confirmed the maternally inherited variant in KCNQ1 gene, and beta-blocker therapy was started. No arrhythmic events were noted. Discussion Detection and careful stratification of foetal heart rate (FHR) is crucial in every pregnancy. Foetal bradycardia can be caused by both maternal and foetal factors. Persistent low FHR should raise a high suspicion for LQTS. The condition may also present with atrioventricular blocks, torsades de pointes, or sudden intrauterine foetal demise. Accurate and early diagnosis of LQTS is essential for implementing appropriate management strategies, which include vigilant monitoring, effective medical treatment, careful planning of delivery, and post-natal care.

A Study of Cardiac Autonomic Neuropathy in Patient with Diabetes Mellitus.

Atherosclerotic coronary artery disease, diabetic cardiomyopathy, and cardiac autonomic neuropathy (CAN) are the three categories into which the cardiovascular consequences of diabetes can be grouped. After all other potential causes have been ruled out, cardiovascular autonomic neuropathy-often referred to as CAN in the literature-is defined as the impairment of autonomic regulation of the cardiovascular system. Finding people with CAN is crucial because, if detected early enough, comprehensive therapies focusing on lifestyle, glucose management, and cardiovascular risk factors can reverse the course of CAN and delay its progression. In order to better understand CAN in individuals with diabetes mellitus (DM) and how it relates to risk factors, the current study was conducted. Sixty consecutive diabetic patients were selected to be included in our study, diagnosed as per the American Diabetes Association (ADA) and the European Association for the Study of Diabetes. The presence of CAN was assessed with the help of Ewing's Battery, composed of five bedside tests. Out of 60 patients, a total of 53 patients (88.3%) with DM had CAN. Of these, 38.3% showed early CAN, 38.3% showed definite CAN, and 7% showed severe CAN. The abnormal E:I (exhalation/inhalation) ratio, noticed in 75% of patients, was the most frequently observed abnormal autonomic function test that tests the parasympathetic nervous system. The ECG's QTc interval prolongation provides good specificity for diagnosing CAN as well as assessing its severity, but the majority of cases showed low sensitivity. Since CAN has a significant association with mortality, every patient diagnosed with DM should be evaluated for CAN at the time of diagnosis as well as on an annual basis thereafter, as recommended by the ADA. Optimal glycemic management and lifestyle modification at the initial stages of diabetes may prevent CAN-related complications.

Low Thyroid Hormones Level Attenuates Mitochondrial Dysfunction and Right Ventricular Failure in Pulmonary Hypertensive Rats.

This study is to investigate the repercussions of hypothyroidism in the pathophysiological progression of pulmonary arterial hypertension (PAH). While the control (CTL, n = 5) male Wistar rats received vehicle, PAH was induced with monocrotaline (MCT group, n = 15). Hypothyroidism was induced in a subset of rats by methimazole 3weeks prior to the MCT injection (MMZ + MCT group, n = 15). Plasma thyroid hormones were measured by radioimmunoassay. Electrocardiographic, echocardiographic, and hemodynamic analyses were performed to evaluate the progression of PAH. Gene expression of antioxidant enzymes and cardiac hypertrophy markers were assessed by qPCR. Mitochondrial respiration, ATP levels, and ROS production were measured in right ventricular (RV) samples. Plasma T3 and T4 decreased in both MCT and MMZ + MCT groups (p < 0.05). Right ventricular systolic pressure (RVSP) increased, and RV - dP/dt, + dP/dt, and contractility index decreased in the MCT versus the CTL group and remained within control levels in the MMZ + MCT group (p < 0.05). Relative RV weight, RV wall thickness, RV diastolic area, and relative lung weight were augmented in the MCT versus the CTL group, whereas all parameters were improved to the CTL levels in the MMZ + MCT group (p < 0.05). Only the MCT group exhibited an increased duration of QTc interval compared to the baseline period (p < 0.05). ADP-induced mitochondrial respiration and ATP levels were decreased, and ROS production was increased in MCT versus the CTL group (p < 0.05), while the MMZ + MCT group exhibited increased mitochondrial respiration versus the MCT group (p < 0.05). Hypothyroidism attenuated the RV mitochondrial dysfunction and the pathophysiological progression of MCT-induced PAH.

The role of mitochondrial dysfunction in the association between trace metals and QTc prolongation in the aged population

This study delves into the relationship between environmental metal exposure and QT interval corrected for heart rate (QTc) prolongation, a critical marker for cardiovascular risk in the elderly. Although the interplay between metal exposure and QTc prolongation is important for predicting sudden cardiac death, it remains underexplored. Our analysis of 6478 participants from the Shenzhen aging-related disorder cohort involved measuring urinary concentrations of 22 trace metals and using mitochondrial DNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Utilizing Bayesian kernel machine regression, and structural equation modeling, we assessed the effects of mixed trace metals on QTc prolongation. Our findings indicated a direct association between certain metals (Sb, Cu, Zn) and a 7 % increase in QTc prolongation risk, while Li, V, and Rb were associated with a 5 % reduction in risk. Elevated levels of V, Ti, and Cr corresponded to higher mtDNA-CN. Notably, restricted cubic splines revealed a U-shaped, nonlinear relationship between mtDNA-CN and QTc prolongation. After adjusting for metal exposure, an inverse correlation was observed between mtDNA-CN and QTc prolongation, suggesting mitochondrial dysfunction as a partial mediator.

Evaluation of the Risk of Malignant Arrhythmia Through Electrocardiography Parameters in Patients with Urinary Stone Disease

Introduction: With a lifetime frequency of 10-15% and a recurrence rate of up to 50% within 10 years, urinary stone disease is a major cause of comorbidity. Recently, it has become widely recognized that urinary system stone disease is not only limited to kidney stone development but is also linked to cardiovascular disease and various other illnesses. Malignant arrhythmias (sudden cardiac death and ventricular arrhythmias) are consequences of coronary artery disease. Despite numerous studies demonstrating that urinary system stone disease is a risk factor for coronary artery disease, no electrocardiographic parameters have been evaluated in this patient group This prospective observational study aims to assess ventricular repolarization parameters using electrocardiography, which are risk indicators for malignant arrhythmias in patients with urinary stones disease. Materials and Methods The study included patients diagnosed with urinary stone disease and healthy volunteers. All patients underwent 12-lead electrocardiography. The electrocardiographys were evaluated for QTc interval, QTc dispersion, T peak-end interval, and Tp-e/QTc, and compared with the control group. Results: When comparing the QTc interval, QTc dispersion, T peak-end interval, and Tp-e/QTc parameters between the patient and control groups, no statistically significant differences were found. Conclusion: Contrary to existing knowledge, this study found that malignant arrhythmias in patients with urinary stone disease were not significantly different from the normal population.

The value and accuracy of intracoronary electrocardiogram in the diagnosis of myocardial ischemia in coronary heart disease.

Although intracoronary electrocardiography (IC-ECG) offers direct electrophysiological insights into myocardial ischemia caused by insufficient coronary blood supply, compared to common diagnostic methods like electrocardiography (ECG), it lacks widespread adoption and robust clinical research. To analyze the value and accuracy of intracoronary electrocardiogram in myocardial ischemia diagnosis in coronary heart disease patients. Three hundred patients treated at our hospital were included in the study. Patients were categorized into non-ischemic group A (Fraction Flow Reserve [FFR] > 0.8) and ischemic group B (FFR < 0.75) based on FFR examination results. Both groups underwent IC-ECG examination. The ischemic group received percutaneous coronary intervention (PCI) treatment followed by another FFR examination, dividing them into non-ischemic subgroup B1 (FFR > 0.8) and ischemic subgroup B2 (FFR < 0.75). Both subgroups underwent IC-ECG examination. Receiver operating curves were constructed using FFR to assess the clinical utility of different IC-ECG parameters. Group A patients showed a significant decrease in ST-segment shift at J-point, ST-segment integral, T-peak, T-wave integral, and T-peak to end-time, while the Corrected Q-T interval (QTc-time) was significantly higher in the B group (p< 0.05). The parameters, including ST-segment shift at J-point, ST-segment integral, T-wave integral, T-peak, T-peak to end-time, and QTc-time, were found to have clinical significance in predicting the occurrence of myocardial ischemia (p< 0.05). Intracoronary electrocardiogram QT interval dispersion and Q-T peak (QTp) interval dispersion have a high diagnostic accuracy for myocardial ischemia in coronary heart disease.

Detection of distant relatedness in biobanks to identify undiagnosed cases of Mendelian disease as applied to Long QT syndrome

Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we develop a generalizable method of genotype inference based on distant relatedness and deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identify 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncover recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identifies 22 additional subjects sharing this haplotype, which we confirm to carry p.Asp76Asn. Referral and non-referral carriers have prolonged QT interval corrected for heart rate (QTc) compared to controls, and, among carriers, the QTc polygenic score is independently associated with QTc prolongation. Thus, our innovative analysis of shared chromosomal segments identifies undiagnosed cases of genetic disease and refines the understanding of LQT5 penetrance and phenotype.

Comparison of Systemic Exposure Between Epinephrine Delivered via Metered-Dose Inhalation and Intramuscular Injection.

Background: Primatene® MIST, an epinephrine metered-dose inhaler (MDI), has long been questioned by some medical professionals for asthma treatment despite having been approved by the Food and Drug Administration. One of the primary reasons for their concerns stemmed from potential cardiovascular complications following epinephrine administration. However, the majority of documented cardiovascular complications seemed to occur following the injection route of the epinephrine. The aim of this study was to evaluate the systemic exposure of epinephrine delivered through different administration routes and to understand its relationship with cardiovascular effects. Since albuterol inhalers are commonly recommended for asthma, albuterol was also studied as a comparator drug. Method: A randomized, evaluator-blinded, three-arm crossover study was conducted in 28 healthy adult subjects to compare the profiles of systemic exposure for epinephrine delivered by MDI versus epinephrine intramuscular (IM) injection and albuterol MDI. Serially sampled plasma epinephrine and albuterol levels were measured and compared between treatment groups. Safety was assessed by adverse events, serial vital signs, electrocardiograms (ECGs), and clinical laboratory tests obtained at each crossover dosing visit. Results: Systemic exogenous drug exposure for inhaled epinephrine MDI (39 pg/mL × hour) was ∼9 times lower than that of epinephrine IM (435 pg/mL × hour) and 122 times lower than that of albuterol MDI (3453 pg/mL × hour) after dose normalization. The Cmax in epinephrine MDI (345 pg/mL) was approximately half of that of epinephrine IM (816 pg/mL) and that of albuterol MDI (681 pg/mL). Plasma drug concentrations for epinephrine MDI dropped rapidly to baseline (∼0.6 hour), while epinephrine IM took ∼8 hours, and albuterol MDI required more than 24 hours. Epinephrine MDI and albuterol MDI resulted in minimal, clinically insignificant changes in vital signs and ECGs, whereas epinephrine IM led to mild transient increases in systolic blood pressure, heart rate, and corrected QT interval. Conclusion: Epinephrine MDI (Primatene MIST) had ∼9 times lower systemic drug exposure (SDE) than that of epinephrine IM and ∼122 times lower than that of albuterol MDI. The lower SDE of inhaled epinephrine also correlated with reassuring safety findings, with no significant cardiovascular adverse effects found, compared with transient effects seen after IM epinephrine. Clinical trial registration number: NCT04207840.

Relevance of accurate QT correction in the assessment of long QT syndrome

BackgroundLong QT syndrome (LQTS) is a genetic cardiac disease, where the corrected QT (QTc) interval is prolonged. It can cause arrhythmias and lead to a sudden cardiac death. Duration of the QT interval depends on the heart rate and this dependency is treated with QT correction. However, the current QT correction methods have well known problems and limitations. ObjectiveWe study the relevance of QT correction method in evaluating the risk of LQTS. We evaluate the reliability of the present and recently developed QT correction methods to discriminate LQTS subjects from healthy controls. MethodsWe use the clinically prevalent QT correction methods, particularly Bazett and Fridericia, in comparison with the recently developed AccuQT method. The data of healthy controls and LQTS subjects is extracted from the Rochester THEW database. The analysis accounts for sex, major LQTS subtypes, and beta-blocker treatment. ResultsQT values corrected with AccuQT discriminate the healthy and LQTS samples with the best accuracy, leading to (TP, TN) = (0.87, 0.65) with the conventional 450 ms threshold for LQTS. Fridericia correction yields lower sensitivity (0.71), but comparable balanced accuracy, whereas Bazett shows significantly less accurate results due to overcorrection at lower heart rates. ConclusionThe selected QT correction method is important in the identification of LQTS. In particular, the use of Bazett correction should be questioned. Fridericia correction yields good results with respect to its simplicity. AccuQT has the best accuracy out of all the methods for LQTS discrimination. For practical applicability, however, AccuQT needs further validation in realistic clinical conditions.

Cardiotoxic Effects of Lachesis acrochorda Snake Venom in Anesthetized Wistar Rats.

Ophidism is a public health problem in tropical countries, occurring predominantly in rural areas. In Colombia, among the species responsible for snakebite envenomation, inflicting high mortality, is the Chocoan bushmaster, Lachesis acrochorda, better known locally by the names "verrugosa (warty)" and "pudridora (rot-causing)". In this research, the cardiotoxic effect of the venom of L. acrochorda in male Wistar rats weighing 230 ± 20 g was evaluated. A statistical design of randomized blocks was implemented with three treated groups, injected with lyophilized venom (doses of 3.22 μg/g, 6.43 μg/g, 12.86 μg/g), and a control group injected with 0.9% saline solution. Electrocardiographic (ECG) recordings were taken from the anesthetized animals, revealing an increase in the amplitude of the P and T waves and an increase in the duration of the QT intervals in the electrocardiographic recordings. These increases were not observed in the control biomodels. In the analysis of the CK and CK-MB enzyme levels, increases were also observed in the levels of cardiac isoenzymes in the injected animals, but none in the control animals. The histopathological analyses carried out reveal that the injected animals showed effects such as interfibrillar and perivascular edema, cellular shortening of the cardiomyocytes, foci with tissue destructuring, and necrosis with contraction bands. In conclusion, the venom of the Lachesis acrochorda snake increases the P and T waves and the QT interval and increases the CK and CK-MB enzymes in the blood. Additionally, it causes interfibrillar and perivascular edema in the cardiac tissue, cardiocytolysis, and contraction bands.

The Kv4 potassium channel modulator NS5806 attenuates cardiac hypertrophy in vivo and in vitro

The compound NS5806 is a Kv4 channel modulator. This study investigated the chronic effects of NS5806 on cardiac hypertrophy induced by transverse aortic constriction (TAC) in mice in vivo and on neonatal rat ventricular cardiomyocyte hypertrophy induced by endothelin-1 (ET-1) in vitro. Four weeks after TAC, NS5806 was administered by gavage for 4 weeks. Echocardiograms revealed pronounced left ventricular (LV) hypertrophy in TAC-treated mice compared with sham mice. NS5806 attenuated LV hypertrophy, as manifested by the restoration of LV wall thickness and weight and the reversal of contractile dysfunction in TAC-treated mice. NS5806 also blunted the TAC-induced increases in the expression of cardiac hypertrophic and fibrotic genes, including ANP, BNP and TGF-β. Electrophysiological recordings revealed a significant prolongation of action potential duration and QT intervals, accompanied by an increase in susceptibility to ventricular arrhythmias in mice with cardiac hypertrophy. However, NS5806 restored these alterations in electrical parameters and thus reduced the incidence of mouse sudden death. Furthermore, NS5806 abrogated the downregulation of the Kv4 protein in the hypertrophic myocardium but did not influence the reduction in Kv4 mRNA expression. In addition, NS5806 suppressed in vitro cardiomyocyte hypertrophy. The results provide novel insight for further ion channel modulator development as a potential treatment option for cardiac hypertrophy.